Pteroic acids and process of preparing same



Patented June 3, 1952 UNITED. STATES PATENT oFFrc-s r'renoio ACIDS AND BROCES'SOF PREPARING- SAME Coy .W; Waller and John H. Mowat, Pearl River,

N. Y., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Original application July 23, 1945,

Serial 180,606,704. Divided and this applic vtion April 12, 1947, Serial No. 741,003

in which X is a halogen and R is .--,Ol-I or ---OR', B being an alkyl radical. Two hydrogen atoms of the pyrazyl ring of the illustrated product or one of its tautomeric or resonant forms, as. the case may be, are removed,'by oxidation or otherwise, to yield the following compounds:

OH A N COR L L Acid salts of these compounds may be prepared y t at ent with st on .inin ral acids Such as hydrochloric, sulfuric, and the like. Salts with cations may also be obtained by treatment of the compounds with a suitable alkali, such as an alkali metal hydroxide, ammonia, an amine, or the like. Other metal salts of cations such as zinc, silver, nickel, copper, magnesium, barium, and the like may be obtained therefrom by double decomposition methods, foregample by treatin a solution of an alkali metalsalt of the compound with a soluble salt of the desired cation.

Generally speaking, the compounds of the pres ent invention are yellow to reddish-brown crystalline solids, difiiculty soluble inwater and organic solvents. Some possess vitaminelike properties and appear to be necessaryfor, or stimulate the growth of, certain bacteria and higher forms of animal life. Other compoundsin the-series 2. possessproperties which make them of value in still other ways.

Of the reactants, 2,4,5-triamino-6-hydroxypyrimidine is a known compound and maybe prepared by methods which have been described in the chemical literature. As is also well known, this compound may exist in one or more tautomeric forms, such as:

he l t is known as t5-tr amin r i Qne- 6. Wh ther or not the com ound exists i th keto form or the enol form probably depends upon e pH i h med m n which th oo pound is'dissolved. In acid media the compound most likely exists in keto form whereas in alkaline media it exists as th @Iiol form As will be understood by those inthe art, either of the tautomeric forms may be l ed inthe same chemical reactions, in like manner and'reierence'hereat to e se of onetautome c iorminclu the use of theothers.

he preferre alph e a-dihalop p o a d hyde isjalpha, beta-dibromopropionaldehyde, .although,as illustrated in, the specific examples, other dihalogenated propionaldehydes may be used. 'It will also be noted that acetals of dihalopropionaldehydes may also be used in the reactionl As an equilibriumexists between the free aldehyde and its acetal in-solution, it is believed that the actual reactant is the aldehyde itself. Accordingly, when reference is made hereinafter,

and in the claims, to the use of a dihalopropionaldehyde, such reference is .intendedto include the equivalent use of the corresponding .dihalopropid ldeii m a s 7 I The aminobenzoylreactants include, any ortho, meta, or paraaminobenzoic acid, and salts, esters,

and otherrelated derivatives thereof. The biological activity of theresulting produotdepends,

in large measure, upon the'particular aminobenzoyl compound employed in" the reaction. For example, Whenp-aminobenzoic acid or itssalts are used, the resulting product is biologically active as an essential growth factor for Streptococcus fecalis R but is, however, inactive with certain other organisms for which other compounds of the invention show activity.

The compounds that are formed when using esters of p-aminobenzoic acid, such as the methyl,

- ethyl, butyl, :benzyl, and the like, esters, do not It' is possible, 'how- 1 appear to possess the same biological activity, being ineffective, in promoting the growth of f. Streptococcus fecalis R and certain other organf isms with which these 7, compounds have been I tested at the present time. ever, that these particular compounds may be of 'value in experimental medicine in other ways.

The reaction may be conducted by miidng all of time or the dihalopropionaldehyde may 'be first reacted with one of the other two reactants before adding the third to the reaction mixture.

the three essential reactants together at the same 1 ly the crystal phasepresented gave only a centered optic axis figure with 2V nearly. 90. Beta (18) was found to be 132010.005. The particular crystals examined were thin and diamond shaped'and showed symmetrical extinction with some residual slight blue-gray transmission at the extinction .position. The crystals decomposed, when heated, without melting.

The free acid is insoluble in aqueous solutions "of strong acids and is extremelyinsoluble at a pl-l of about3; but may be recrystallized from 7 The reaction may take place over a wide range 5 of temperatures, from 2 or 3 C. up to 100 C. or

higher. Likewise, the reaction will take place under a widerangeof pH conditions, there ap- I pearing to be no limiting acidity or alkalinity. 7 Best results appear to be obtained, however, within the range of pH 3 to pH 5. r The reaction is usually conducted withthe reactants dissolved or suspended in a solvent such as'water, ethyl alcohol, acetone, benzenep carbontetrachloride, chloroform, etc. or mix.-

, tures thereof. 7 V V I I I As previously noted 'thefirst product of; the

reaction appears to be an unstable dihydro form and, 'in the presence of oxidizing agents, two

hydrogen atoms from the pyrazine nucleus are split out to form the aromatic form of the product. Simple exposure of the product to the air will bring'about this, oxidation in a short time. Other oxidizing agents, such as elemental iodine, will'produce thesame result and it may 3N hydrochloric acid. Itis soluble in aqueous solutions of bases with the formation of a monobasic or d'ibasic salt depending on the concentration and strength of base used.

The acid salts of the compound are obtained by'treatment of the product with strong acids.

' The'hydrochloride was prepared and had a refractive index parallel to the width of the crystals of 1.86:0.01 and a refractive index parallel to the length of the crystals of 145910.003. The particular crystals examined were found to have a tinycolumnar form, 10 to 20 long and l wide. w v

The compound of this example was found to I be an essential growth factor for Streptococcus fecalis R, but not for Lactobacillus casez'. It did not promote the growth of chicks or the forma- I tion or haemoglobin.

be of advantage to .use such oxidizing agents under some conditions. jThefluse of oxidizing agents-of this-type, however, is not a part of the present-invention and forms the subject matter .of an application by Donna B. Cosulich, Serial No. 689,821, filed August; 10, 1946, now abandoned.

. The invention will now be described in' greater 1 particularity by means'of the 7 following examples in which various reaction conditions and-reactantsare shown. It will be understood, of course, that the invention is not limited to the particular details of these examples since other 7 reaction conditions; and 1 reactants within the: V skill of theart may be employed to produce new and'usefulcompounds falling within the scope of -the "present invention. All parts are by 7 weight unless otherwise indicated.

' Example 1 r V Oneypart by weight of 2,4,5-triamino-6 hy- 'droxypyrimidine and 1.0 part of p-aminoben-j 'zoic acidwere dissolved in 100 partsby volume product obtained had the following structure:

NHr-L i N l The product was obtained in the form of light yellow crystals. When examined microscopical- Example 2. 1 V.

The procedure of Example 1 was repeated using in place of 'p-aminobenzoic acid an equivalent amount of ethyl p-aminobenzoate. The

resulting compound had the following structure:

V N g N Tommi 7 002m NE -k V '1 V V e N \N/ This compound was found to be less active.

than the product of Example 11 as a growth factor under the conditions .of the test when tested against Streptococcus fecalis R;

We claim: f 1. Compounds selected from the group convsisting of those having" the general formula v, N t COR 1 Tommi-O k A v in which R is a radicalof the group consisting of OH and OR, B. being an alkyl radical, and

the saltsof suchcompounds. 1

2. Acompound having the formula,

N oruru1 3-coou I '3. The metal salts of the compound of "claim 2. 4. A compound having the formula v Toning 7 00,11,

5. A method which comprises mixing together 2,4,5-triamino-6-hydroxypyrimidine, alpha, betadihalopropionaldehyde, and in aromatic amine of the group consisting of aminobenzoic acid, its salts and its esters, and after reaction thereof recovering a compound having the formula COR N Tommi-O NHF COR in which R is a radical of the group consisting of OH, OMe, and OR', R being an alkyl radical and Me being a cationic salt forming radical.

7. A method which comprises mixing together 2,4,5triamino6-hydroxypyrimidine, alpha,betadibromopropionaldehyde and an aromatic amino of the group consisting of aminobenzoic acid, its salts and its esters, and after reaction thereof recovering a compound having the formula COR N k A in which R is a radical of the group consisting of -OI-I, OMe, and OR', R being an alkyl radical and Me being a cationic salt forming radical.

8. A method which comprises mixing together 2,4,5-triaminoG-hydroxypyrimidine, alpha, betadichloropropionaldehyde and an aromatic amine 6 of the group consisting of aminobenzolc acid, its salts and its esters, and after reaction thereof recovering a compound having the formula OH I N O O R T -C5 m in which R is a radical of the group consisting of OH, OMe, and OR', R being an alkyl radical and Me being a cationic salt forming radical.

9. A method which comprises mixing together in an aqueous solvent and a hydrogen ion concentration within the range of pH 3 to pH 5 2,4,5- triamino6-hydroxypyrimidine, alpha, beta-dibromopropionaldehyde. and p-aminobenzoic acid and after reaction thereof recovering a compound having the formula N KY j-GH NH-OOOOH NH N/\N 10. A compound selected from the class consisting of those having the following structure:

N (\f j-OH NH -QC 0 OH H2N '\N/\N/ and the alkali metal salts thereof.

11. Hydrohalide salts of the compound having the formula:

COY W. WALLER. JOHN H. MOWAT.

REFERENCES CITED The following references are of record in the file of this patent:

Angier et al., Science (No. 2683), 103, 667-669 (1946).

on I N K] TOHr-NBE-QOOOH H2NJ\N \N/ 

1. COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE GENERAL FORMULA
 5. A METHOD WHICH COMPRISES MIXING TOGETHER 2,4,5-TRIAMINO-6-HYDROXYPYRIMIDINE, ALPHA, BETADIHALOPROPIONALDEHYDE, AND IN AROMATIC AMINE OF THE GROUP CONSISTING OF AMINOBENZOIC ACID, ITS SALTS AND ITS ESTERS, AND AFTER REACTION THEREOF RECOVERING A COMPOUND HAVING THE FORMULA 